Discussion
In this large retrospective study of a cohort of individuals newly diagnosed with type 2 diabetes in England, we found that the presence of microvascular and macrovascular disease varied substantially by glycemic status before diagnosis. Compared with individuals with glycemic levels within the normal range within 3 years before type 2 diabetes diagnosis, individuals with prior pre-diabetes and those without glycemic testing were significantly more likely to have microvascular disease at the time of type 2 diabetes diagnosis. Individuals with prior pre-diabetes were also more likely to have a previous diagnosis of acute coronary syndrome at the time of diagnosis. Conversely, individuals with prior pre-diabetes were less likely to have cerebrovascular and peripheral arterial disease compared with those who had glycemic values within the normal range before type 2 diabetes diagnosis. There were only small variations in these findings across various pre-diabetes diagnostic criteria including WHO/IEC, ADA, and NICE. Individuals who had a diagnostic label for pre-diabetes in their health records had lower odds of microvascular and macrovascular diseases compared with those with pre-diabetes without a diagnostic code.
In this study, we specifically focused on individuals who eventually progressed to type 2 diabetes to examine how prior glycemic testing and status is linked to vascular disease in a population which would benefit the most from preventative interventions. Over one-third of individuals in this study were diagnosed with either retinopathy or nephropathy at the time of type 2 diabetes diagnosis, one-fifth had at least one macrovascular disease, and half of them had at least one microvascular or macrovascular disease. These findings correspond with previous studies reporting a high burden of vascular disease among newly diagnosed individuals with type 2 diabetes,39–41 and support existing evidence suggesting that in individuals with pre-diabetes vascular disease might occur even before progressing to type 2 diabetes.18 19 Pre-diabetes is associated with an excess risk for the development of both macrovascular and microvascular diseases with a continuum of risk across the glycemic range of pre-diabetes.6 16 42 In the majority of people who progress to type 2 diabetes, an abrupt increase in glycemic measures has been described within 2 to 3 years before diagnosis.6 30 In our study, the higher burden of retinopathy among individuals with pre-diabetes compared with individuals with normoglycemia might be explained by prolonged exposure to mild hyperglycaemia.
Accordingly, individuals with glycemic values within the normal range might include a subgroup of individuals with a more rapid progression to type 2 diabetes or could represent people with a similar glycemic trajectory leading to diabetes but with a diagnosis earlier in the natural history of the disease or most likely a combination of these mechanisms.6 43 It is also important to note that while more than 80% of this group had recorded measures of FPG in the 3 years before the diagnosis of type 2 diabetes, only less than a quarter (23.7%) had recorded measures of more than one type of glycemic test, which might suggest that this group was less frequently and accurately tested. Considering the predominant use of FPG, more prone to intra-person variability as compared with HbA1c, and the intermittent nature of glycemic values during the pre-diabetes status and in general in the 3 years before progression to type 2 diabetes,43 44 a proportion of this group might have been misclassified with glycemic values within the normal range but this reflects detection patterns in real-world settings.
Importantly, 59% of individuals did not have a recorded glycemic measurement in the 3 years before type 2 diabetes diagnosis. Individuals without glycemic measurements had a notably higher mean HbA1c following type 2 diabetes diagnosis compared with those with glycemic testing (with or without pre-diabetes), potentially indicating late diagnosis of type 2 diabetes and leading to delayed treatment. The clinical characteristics of these people are compatible with at least two explanations: First, these people may be less health conscious and have a worse adherence with preventive procedures reflected by their higher prevalence of smoking and a lower number of primary care visits. Second, individuals without previous glycemic testing before their diagnosis of type 2 diabetes might have had lower vascular risk, as reflected by lower unadjusted prevalence of macrovascular disease at time of diabetes diagnosis, and lower number of other comorbid conditions. This may have resulted in fewer contacts with primary care and missed opportunities for screening. The considerably higher mean HbA1c at the time of diagnosis in this group may reflect a diagnosis at a later stage compared with the other groups and explain the higher prevalence of retinopathy. This is also in line with previous findings showing that glycemic testing and clinical management might potentially delay the diagnosis of diabetes and potentially its complications.45
The differences for nephropathy were less pronounced between the glycemic groups compared with that for retinopathy. These findings suggest that the association between pre-existing pre-diabetes and nephropathy might not be as strong as that for retinopathy. This is in line with the findings of a recent meta-analysis that concluded that the association between pre-diabetes and nephropathy was significant but modest, and this might be partially explained by underlying confounding or common causes contributing to both hyperglycemia and kidney disease.6 46 A small proportion of individuals (5.4% considering the whole sample) had both retinopathy and nephropathy in this study, potentially indicating prolonged exposure to chronic hyperglycemia or non-diabetic glomerular disease in some individuals that, at least partly, may explain the different patterns of renal involvement.47 48
We only found small variations in our findings across pre-diabetes subgroups defined by WHO/IEC, NICE, and ADA, suggesting that when focusing on the proportion of the pre-diabetes population who eventually progresses to type 2 diabetes, differences are less pronounced then what has been found in studies focusing on the whole pre-diabetes population, including those who will never progress to type 2 diabetes.12
We found that individuals with pre-diabetes detected before the diagnosis of type 2 diabetes were more likely to have a previous diagnosis of acute coronary syndrome but were less likely to have cerebrovascular and peripheral arterial disease at time of type 2 diabetes diagnosis. These findings correspond with previous studies showing that chronic hyperglycemia contributes to the pathogenesis of macrovascular dysfunction.6 14 16 17 Hyperglycemia has been shown to be strongly associated with an increased risk of acute coronary syndrome.6 49 Individuals with acute coronary syndrome have increased prevalence of pre-diabetes and the risk of mortality for those hospitalized with acute coronary syndrome with hyperglycemia is also higher.6 49 However, the association between pre-diabetes and cerebrovascular disease is less clear. For instance a meta-analysis found that the associated risk of cerebrovascular disease among those having pre-diabetes is modest.50 These findings are also compatible with a potential surveillance bias: people with any cardiovascular disease are more likely to be screened for type 2 diabetes and intermediate hyperglycemia compared with the general population, potentially resulting in an earlier diagnosis of type 2 diabetes. This bias might have had a greater influence on findings where the link between pre-diabetes and the outcome is weaker and may have changed the direction of the association (ie, cerebrovascular disease as compared with acute coronary syndrome).
Strengths and limitations
To our knowledge, this is the first large population-based study to examine associations between glycemic status before type 2 diabetes diagnosis and the presence of microvascular and macrovascular disease in individuals newly diagnosed with type 2 diabetes. Our findings provide further evidence that pre-diabetes has significant clinical implications for microvascular and macrovascular diseases and type 2 diabetes outcomes. We used routinely collected primary and secondary care data representative of the English population to better understand these associations in real-world settings. While the implementation of a national retinopathy screening program in the UK and the increased surveillance within the QOF ensured good quality data for the diagnosis of retinopathy and nephropathy, we did not include diabetic neuropathy in our analyses because the diagnosis and coding of this condition appears suboptimal in primary care settings in England.51 We could not assess the duration individuals remained in the pre-diabetes state before progressing to type 2 diabetes, and the focus of the study was to identify the recording of pre-diabetes before type 2 diabetes diagnosis. Additional study limitations include the presence of missing data for clinical variables such as blood pressure, BMI, total cholesterol, and HbA1c. However, we overcame the latter issue by using multiple imputation by chained equations. It was not possible to assess differences in adherence to lifestyle interventions, as we did not have data on diet and physical activity. Finally, when using routinely collected data, concerns have been raised about miscoding, misclassification, and misdiagnosis. However, CPRD is subject to regular quality checks and is widely used for health research.25
Implications for clinical practice
Microvascular and macrovascular diseases were present in 37%–24% of people with newly diagnosed type 2 diabetes, with over half not having any glycemic measurement within 3 years before their diagnosis. While there are many unanswered questions regarding its detection, pre-diabetes has significant clinical implications for microvascular and macrovascular diseases and type 2 diabetes outcomes. A major consideration is whether targeted preventive strategies that identify individuals with pre-diabetes for interventions would provide opportunities for vascular risk reduction,21 42 52 considering that major benefits are likely to occur from early diagnosis and treatment.45 While discussions on the pathophysiological differences between pre-diabetes subtypes continue, there have been calls to move away from a glucocentric definition toward a multifactorial detection strategy for pre-diabetes that reflects the presence of other risk factors for type 2 diabetes as well as early manifestation of vascular disease.6 53